Sulfadimethoxine, methods for their preparation and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to new O-substituted or-unsubstituted 6-sulfonamide-1,3-doxepin-5-tins of formula I, where R1and R2is a hydrogen atom, straight or branched C1-C4alkyl, R3is unsubstituted or o-, m - or n-substituted phenyl group, where the Deputy is alluminare, Y is a hydrogen atom or a straight or branched C1-C4alkyl, and their pharmaceutically acceptable salts, having hypoglycemic activity, processes for their preparation and pharmaceutical compositions based on them. These compounds derived from 6-amino-1,3-dioxan-5-ol, tetrahydro-6N-/1,3/-doxepin/5,6-d/oxazole, 5,6-epoxy-1,3-dioxetane or N-sulfonylurea-1H, 4H-/1,3/-doxepin/5,6-d/ azirine as starting materials.

< / BR>
6 C. and 7 C.p. f-crystals.

The invention relates to new sulfamethoxazol, methods and intermediate products for their production, their salts, pharmaceutical preparative forms containing the new connection.

New sulfadimethoxine General formula I.

< / BR>
where

R1and R2represent a hydrogen atom, a straight or branched alkyl with 1 to 4 atoms means a straight or branched alkyl with 1-4 C atoms, straight or branched from mono - to perfluoroalkyl with 1 to 4 C atoms, and o-, m - or p-substituted phenyl group

< / BR>
where

X is a hydrogen atom, a lower straight or branched alkyl with 1-4 C atoms, triptorelin group, a halogen atom (chlorine, fluorine, bromine, iodine), hydroxy, alkoxy, amino, alkyl - or dialkylamino, acylamino or hydroxyamino group;

Y represents a hydrogen atom, a lower straight or branched alkyl with 1-4 C atoms, benzyl or sulfonyl group

SO2R3< / BR>
where R3has the above significance, or is an acyl group

-CO-R4,

where

R4is a lower straight or branched alkyl with 1-4 C atoms or the benzyl group,

and their physiologically acceptable salts are still unknown.

These compounds have valuable pharmacological properties, particularly hypoglycemic activity, regardless of the route of administration, which may be intravenous, subcutaneous or oral. Hypoglycemic activity determined using standard methods on warm-blooded animals, such as mice.

The compounds of General formula I, the alkyl and alkoxy are methyl, ethyl, propyl, isopropylmalate, isobutoxy group. Allgroups is derived from aliphatic, arylaliphatic or aromatic carboxylic acids, for example formic acid, acetic acid, propionic acid, butyric acid, phenylacetic acid or benzoic acid.

The new compounds of General formula I form salts, which are also the object of the present invention. Examples of such salts are salts of alkali and alkaline earth metals, such as salts of sodium, potassium, magnesium or calcium.

The new compounds of General formula I can be obtained by reacting compounds of General formula II

< / BR>
where

R1, R2and Y have the meanings described above,

with a reactive derivative of sulfonic acids of General formula III

R3SO2-Z

where

R3has the above meanings and

Z represents a halogen atom such as fluorine, chlorine, or-OSO2R3group, where R3has the above significance, in vodosmeshivayuschego or odonatologica inert organic solvent in the presence or absence of water in the presence or absence of an inorganic or organic acid acceptors at a temperature of from -50oC to +50

Suitable inert solvents are, for example, hydrocarbons, such as toluene or xylene, lower alcohols of up to 6 C atoms, such as methanol or ethanol, ethers, such as diethyl ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride or chloroform, lower ketones to 6 C atoms, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, esters of carboxylic acids, such as ethyl acetate, NITRILES of carboxylic acids, such as dimethylformamide or NMRT, sulfoxidov, such as dimethylsulfoxide or sulfones, such as sulfolane.

Suitable inorganic bases are the hydroxides of alkali and alkaline earth metals, acid carbonates, carbonates or phosphates, may be used compounds of sodium or potassium, and magnesium or calcium.

Suitable organic bases are tertiary amines, such as triethylamine, dimethylaniline, pyridine, DBN or DBU.

Suitable parent compounds of General formula II are compounds that are respectively substituted in accordance with the determination of the values of R1, R2and V, as shown in formula I. One such group starting compounds are 6-amino-1,3-dioxan-5-Ola, Cote 4389526) and ammonolysis of the epoxy-1,3-dioxetanes (M. Sovak and R. Ranganathan, EP 33426; A. V. Rama Rao et al., Indian J. Chem. 22B (1983) 419).

The new compounds of General formula I can also be obtained by the interaction of oxazolines General formula IV

< / BR>
where

R1, R2and R4have the above meanings, with a reactive derivative of sulfonic acids of General formula III, where R3and Z have the above meanings, in a non-aqueous inert organic solvent in the presence of an inorganic or organic acid acceptor and optionally carrying out the hydrolysis or alcoholysis of the obtained compounds of General formula I (Y=-COR4in derivatives of the formula I (Y=H) and, optionally, converting the obtained compounds with inorganic bases and metal alcoholate in pharmaceutically acceptable salts. The method of carrying out this process is identical to the first method except that it is carried out in non-aqueous environment.

Suitable parent compounds of General formula IV are compounds that are respectively substituted in accordance with the determination of the values of R1, R2and R4as shown in the formula I. They can be easily obtained by cyclization with dehydrohalogenating corresponding 6-acylamino-5-chloro-1,3-dioxetanes (M. Dumic' et al., Org is received by reaction of epoxides of the General formula V.

< / BR>
where

R1and R2have the above values,

with sulfonamides of General formula VI

R3SO2NH2< / BR>
where

R3has the above value,

by heating the two reactants in the absence or in the presence of inert organic solvents, such as, for example, aromatic solvents such as toluene or xylene, chlorinated hydrocarbons such as methylene chloride, chloroform or dichloroethane, esters of carboxylic acids, such as ethyl acetate, ethers, such as diisopropyl ether or dioxane, amides, such as dimethylformamide, dimethylacetamide or NMRT, sulfoxidov, such as dimethylsulfoxide, or sulfones, such as sulfolane at a temperature of 25oC to 300oC and preferably from 100oC to 200oC and, optionally, converting the obtained compounds with inorganic bases or metal alcoholate in pharmaceutically acceptable salt.

Suitable parent compounds of General formula V are compounds that are respectively substituted in accordance with the determination of the values of R1and R2in the formula I. They can be easily obtained through education of epoxy compounds is 1980, 810)

According to the fourth method, the new compounds of General formula 1 can be obtained by hydrolysis of N-sulfonylacetonitrile General formula VII

< / BR>
where

R1, R2and R3have the above values,

in water or in vodosmeshivayuschego organic solvents in the presence of inorganic bases at a temperature of from 0oC to 150oC, preferably from 50o100o, and, optionally, converting the obtained compounds with inorganic bases or metal alcoholate in pharmaceutically acceptable salt.

As organic solvents used alcohols of up to 6 C atoms, such as methanol or ethanol, or tert-butanol, ethers, such as dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride or chloroform, ketones, such as acetone, amides such as dimethylformamide or NMRT, amines, such as pyridine, sulfoxidov, such as dimethylsulfoxide, or sulfones, such as sulfolane. As grounds can be used hydroxides or carbonates of alkali metals such as lithium, sodium or potassium.

Suitable parent compounds of General formula VII are compounds that, when there might be obtained by sulfonation of the corresponding disseminationof (M. Dumic' et al., W. O. 93 04, 067; Tetrahedron Lett. 34(1993) 3639).

Optional new compounds of General formula I obtained in accordance with methods (1-4) of the invention, converted into their pharmaceutically acceptable salts by reaction of compounds of General formula I with an equimolar amount of inorganic bases, alkali metal hydroxide, e.g. sodium hydroxide or alcoholate of an alkali metal such as sodium methylate, in inert organic solvents, such as methanol, ethanol, acetone, toluene, diisopropyl ether.

The new compounds of General formula I obtained in accordance with the methods of the invention, or their pharmaceutically acceptable salts exhibit hypoglycemic activity from large to strong model of diabetes in mice induced streptozotocin, regardless of the route of administration, which may be intravenous, subcutaneous or oral. For example, 4 hours after subcutaneous injection of CIS-6-sulfonylamino-1,3-dioxan-5-ol in the dose of 20 mg/kg to mice with diabetes induced streptozocin, the concentration of glucose in blood is decreased by 16.6%, i.e. the level of glucose is 83.4% of the level present in untreated animals with hyperglycemia.

Due to effektivnye hypoglycemic agents and using conventional methods of pharmaceutical technology, they can turn into suitable pharmaceutical formulation, such as tablets pilley, powders, capsules, granules, solutions, etc. with short-term or prolonged activity for diabetes diabetes mellitus.

The present invention is illustrated, but not limited to, the following examples.

Example 1

A mixture of TRANS-6-amino-1,3-dioxan-5-ol (0,30 g), 4-acetyl-aminobenzenesulfonamide (0,58 g), pyridine (0,40 ml) and methylene chloride (10.0 ml) is stirred at a temperature of 0oC for 60 minutes. After evaporation of the solvent in vacuo, the residue chromatographic on a column of silica gel with elution by ethyl acetate.

Get TRANS-6-(4-acetamidobenzenesulfonyl)-1,3 - dioxan-5-ol. So pl. 210-211oC/ethyl acetate-methanol (9,5:0,5).

Example 2

A mixture of CIS-2-methyl-3a, 4,8,8 a-tetrahydro-6H[1,3] -dioxano [5,6-d] oxazole (1,00 g), 4-acetamidobenzaldehyde (1.50 g), pyridine (1.05 ml) and methylene chloride (60.0) was stirred at room temperature for 90 minutes, add water (10.0 ml), the mixture is stirred for additional 15 minutes at the same temperature. The product is extracted with methylene chloride, the extract dried over anhydrous sodium sulfate, the methylene chloride evaporated in vacuo, the residue chromatographic on the column with silicone-1,3-dioxan. So pl. 184-186oC/ethyl acetate-methanol (6:1).

A mixture of CIS-6-(4-acetamidobenzenesulfonyl)-1,3-dioxetane (0,150 g), 25% ammonia (3.0 ml) and 96% ethanol (6.0 ml) was stirred at room temperature for 3 hours, evaporated to dryness in vacuo, the residue is recrystallized from ethyl acetate/methanol (1:1) and receive CIS-6-(4-acetamidobenzenesulfonyl)-1,3-dioxan-5-ol, I. pl. 161-163oC.

Example 3

A mixture of 5,6-epoxy-1,3-dioxetane (0.5 g) and 4-acetamidobenzenesulfonyl (0,92 g) is heated in a sealed ampoule at a temperature of 150oC for 15 minutes, cooled to room temperature, chromatographic on a column of silica gel with elution with a mixture of ethyl acetate: methanol (to 9.5:0.5) and get TRANS-6-(4-acetylamino-benzosulfimide)-1,3-dioxan-5-ol, I. pl. 208-210oC/ethyl acetate-methanol (6:1).

Example 4

A mixture of 1-(4-acetamidobenzenesulfonyl)-4,4-dimethyl-1a, 2,6,6 a-tetrahydro-1H, 4H-[1,3]-doxepin [5,6,-b] azirine (0.33 g), potassium hydroxide (0.14 g) and water (2.6 ml) is boiled for 60 minutes, cooled to room temperature, acidified with diluted hydrochloric acid to pH 6.5 and evaporated to dryness in a vacuum. The remainder chromatographic on a column of silica gel with elution with a mixture of ethyl acetate/methanol is a simple methylene-methanol (9:1), TRANS-6-sulfonylamino-2,2-dimethyl-1,3-dioxan-5-ol.

Example 5

A mixture of 1-(4-acetamidobenzenesulfonyl)-1a, a 2,6-tetrahydro-1H,4H- [1,3] -doxepin- [5,6-b] azirine (0,30 g), potassium hydroxide (0.10 g) and water (2.5 ml) is boiled for 60 minutes, cooled to room temperature, acidified with diluted hydrochloric acid to pH 6.5, evaporated to dryness in a vacuum. The remainder chromatographic on a column of silica gel with elution with a mixture of methylene chloride-methanol (10: 1) and receive TRANS-6-(4-acetamidobenzenesulfonyl)-1,3-dioxan-5-ol, I. pl. 209-211oC/ethyl acetate-methanol (1:1) and TRANS-6-sulfanilamide-1,3-dioxan-5-ol, I. pl. 162-164oC/ethyl acetate-methanol (1: 1).

Example 6

To a mixture of CIS-6-amino-1,3-dioxan-5-ol (0,30 g) and pyridine (0,40 ml) in methylene chloride (10.0 ml) at a temperature of 0oC for 90 minutes, added dropwise a solution of 4-acetamidobenzaldehyde (0,58 g) in methylene chloride (35,0 ml), the mixture is stirred for additional 15 minutes at this temperature and then evaporated in vacuum to dryness. The remainder chromatographic on a column of silica gel with elution with a mixture of methylene chloride-methanol (8: 2) and receive CIS-6-(4-acetamidobenzenesulfonyl)-1,3-dioxan-5-ol, I. pl. 159-161oC/acetate-methane is interline. As injection medium is preferably used water which contains customary in the case of solutions for injection of the additive, as a stabilizer, a dissolving agent or a buffer. Such additives are, for example, tartrate and citrate buffer, complexing agents (as ethylenediaminetetraacetic acid and its non-toxic salts and high molecular weight polymers such as liquid polyethylene oxide, to control viscosity. Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acids, high molecular weight fatty acid (as stearic acid), animal and vegetable fats and solid vysokomolochnye polymers (such as polyethylene glycols). Suitable for oral administration the compositions may contain desirable in the case of sweetening and gives taste substances.

These compositions are obtained by mixing the active ingredient with a pharmaceutically acceptable carrier, diluent and other additives.

An example of a pharmaceutical composition in tablet form.

Prepare in the usual mixture of a mixture of 1 kg of active substance of the formula I (compound according to example 5), 1.4 kg of lactose, 1.2 kg of starch, 0,2 CIDA tablet contains 10 mg of active substance.

Oral drops

500 g of A. I. (compound in example 6) dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at 60-80oC. After cooling to 30-40oC added 35 l of polyethylene glycol and the mixture well stirred. Then add a solution of 1750 g of sodium salt of saccharin in 2.5 l of purified water and while stirring add 2.5 l of odorants cocoa and how much glycol to a total volume of 50 l, obtaining a solution for oral administration dropwise containing 10 mg/ml A. I. the resulting solution is poured into suitable containers.

1. Sulfadimethoxine General formula I

< / BR>
where R1and R2is a hydrogen atom, a straight or branched alkyl with 1-4 carbon atoms;

R3- o-, m - or p-substituted phenyl group

< / BR>
where X is a hydrogen atom or aceraminophen;

Y is a hydrogen atom or a lower straight or branched alkyl with 1 to 4 atoms of carbon,

and their pharmaceutically acceptable salts.

2. Connection on p. 1, characterized in that it R1= R2=H, CIS, Y=H, R3=4-CH3CONH-C6H4and its pharmaceutically acceptable salts.

3. Connection on p. 1, characterized in that it R1= R2=H, TRANS, Y= .1, characterized in that it R1= R2=H, CIS, Y=H, R3=C6H5and its pharmaceutically acceptable salts.

5. Connection on p. 1, characterized in that it R1= R2=H, TRANS, Y= H, R3=C6H5and its pharmaceutically acceptable salts.

6. Connection on p. 1, characterized in that it R1= R2= CH3-, Cys, Y=H, R3=4-CH3CONH-C6H4and its pharmaceutically acceptable salts.

7. Connection on p. 1, characterized in that it R1= R2= CH3-, trance, Y=H, R3=4-CH3CONH-C6H4and its pharmaceutically acceptable salts.

8. The method of obtaining sulfamethoxazol General formula I.

< / BR>
where R1and R2represent a hydrogen atom, a straight or branched alkyl with 1-4 carbon atoms;

R3means of o-, m - or p-substituted phenyl group

< / BR>
where X is a hydrogen atom or aceraminophen;

Y is a hydrogen atom or a lower straight or branched alkyl with 1-4 carbon atoms,

or their pharmaceutically acceptable salts under item 1, characterized in that compounds of General formula II

< / BR>
where R1, R2and Y have the above >SO2- Z

where R3has the specified values,

Z is a halogen atom such as fluorine, chlorine, or-OSO2R3group, where R3has the specified values,

in vodosmeshivayuschego or odonatologica inert organic solvents, in the presence or absence of an inorganic or organic acid acceptors at a temperature of from -50 to +50oC and, optionally, the compounds converted into pharmaceutically acceptable salts by treatment with inorganic bases or metal alcoholate.

9. The method of obtaining sulfamethoxazol General formula I

< / BR>
where R1and R2is a hydrogen atom, a straight or branched alkyl with 1-4 carbon atoms;

R3- o-, m-, or p-substituted phenyl group

< / BR>
where X is a hydrogen atom or aceraminophen;

Y is a hydrogen atom, a lower straight or branched alkyl with 1-4 carbon atoms,

or pharmaceutically acceptable salts, characterized in that compounds of General formula IY

< / BR>
where R4- straight or branched alkyl with 1-4 carbon atoms,

R1and R2have the specified values,

interact with reactive derivatives sulfonic inert organic solvent in the presence of an inorganic or organic acid acceptors and, optionally, the compounds of General formula I (Y = COR4), hydrolyzing or alkoholismus to derivatives of the formula I (Y=H) and, if necessary, the obtained compound transform with inorganic bases or metal alcoholate in pharmaceutically acceptable salt.

10. The method of obtaining sulfamethoxazol General formula I

< / BR>
where R1and R2is a hydrogen atom, a straight or branched alkyl with 1-4 carbon atoms;

R3- o-, m-or p-substituted phenyl group:

< / BR>
where X is a hydrogen atom or aceraminophen;

Y is a hydrogen atom, a lower straight or branched alkyl with 1-4 carbon atoms,

or their pharmaceutically acceptable salts under item 1, characterized in that compounds of General formula V

< / BR>
where R1and R2have the specified values,

interact with sulfonamides of General formula VI

R3SO2NH2,

where R3has the specified values,

in the absence or presence of inert organic solvents at temperatures from 25 to 300oC and, optionally, the compounds obtained are converted with inorganic bases or metal alcoholate in pharmaceutically acceptable salt.

12. Connection PP.1-13, possess hypoglycemic activity.

13. Pharmaceutical composition having hypoglycemic activity, containing the active ingredient and an acceptable carriers, diluents, wherein as the active ingredient it contains an effective amount of the compounds of General formula 1 on p. 1.

 

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< / BR>
in which R is tert.butoxy or phenyl, R1is a hydrogen atom or acetyl, and Ar is phenyl, unsubstituted or substituted by a halogen atom, a C1-C4the alkyl or C1-C4alkoxyl
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EFFECT: valuable medicinal properties of compounds.

8 cl, 15 ex

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EFFECT: valuable medicinal properties of compounds.

68 cl, 1 tbl, 6 ex

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EFFECT: valuable medicinal properties of compounds.

61 cl, 1 tbl, 5 ex

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EFFECT: improved and valuable properties of composition.

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4 cl, 6 ex, 10 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), halogen atom and oxygen atom (O); R2 is chosen from consisting of H, halogen atom and N=N; R3 is chosen from group consisting of H and halogen atom; R4 is chosen from group consisting of H, halogen atom, amino and N=N; R5 is chosen from group consisting of H, halogen atom, methoxy, methyl and O; or R1 and R2, or R and R5 are joined and form unsaturated carbon ring; R6 is chosen from group consisting of H, (C1-C6)-alkyl, (C2-C6)-alkenyl, 3-phenyl-2-propin-1-yl, benzyl, benzyl substituted with halogen atom, phenyl or methoxy, CH2-cycloalkyl, CH2-2-furan, -(CH2)2SCH3 and -(CH2)2NHBOC; R7 is chosen from group consisting of H, (C1-C6)-alkyl and cycloalkyl; R8 is chosen from group consisting of benzyl and benzyl substituted with OCH2-phenyl; T represents group of the formula or wherein R9 and R10 represent H; or R9 represents H, and R10 are chosen from group consisting of (C1-C6)-alkyl, (C2-C6)-alkenyl, methyl-substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, cycloalkyl, phenyl substituted with (C1-C6)-alkyl, halogen atom, methoxy, -SCH3 or -N(CH3)2, 1-naphthyl and CH2-CH2-1,3-dioxolane; or R9 and R10 are chosen independently from group consisting of (C1-C6)-alkyl, (C2-C6)-alkenyl, phenyl, phenyl substituted at position 4 with halogen atom, methoxy, -SCH3 or -N(CH3)2 and 1-naphthyl, or its pharmaceutically acceptable salt, hydrate, or its prodrug as carbamate or ester. Also, invention relates to compounds of the formula (Ia) and the formula (Ib) given in the invention description, and to a method for decreasing levels of beta-amyloid, and to their using and to a method for prophylaxis or treatment of Alzheimer's disease, Down's syndrome. Invention provides preparing novel biologically active compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 17 tbl, 278 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of formula (I) as well as to synthesis procedure and application for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis where R1-R11, t, X, Y, Z and n have values specified in the description.

EFFECT: production of macrocyclic compounds used for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis.

41 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

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